The present invention relates to compositions for delivering biologically active agents, particularly therapeutic agents. The compositions comprise a synthetic delivery agent that facilitates oral delivery of the biologically active agent and that may also be used in connection with other routes of delivery. The invention also relates to methods for the preparation and administration of such compositions.
Conventional means for delivering biologically active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically active agents are particularly vulnerable to such barriers. In the delivery of therapeutic agents, barriers are imposed by the body. Physical barriers, such as the skin and various organ membranes, are relatively impermeable to certain active agents, but must be traversed before reaching a target, such as the circulatory system.
Oral delivery would be the route of choice for administering many biologically active agents to animals, including humans, but for barriers that interfere with efficient absorption of these agents. Among the numerous agents that are not typically amenable to oral administration are biologically active peptides, such as insulin, calcitonin, growth hormone, and glucagon-like-peptide-1; polysaccharides and mucopolysaccharides including, but not limited to, heparin and heparinoids; antibiotics; and other organic substance. These agents may be rendered ineffective or may be destroyed in the gastrointestinal (GI) tract by acid hydrolysis, enzymes, electrostatic charges, or the like, or may simply not be absorbed.
Many delivery agents are fairly hydrophobic, whereas many bioactive agents are hydrophilic. This difference in solubility characteristics between the delivery agent and the bioactive agent can be problematic in designing commercially acceptable dosage formulations that exhibit biological activity in vivo. Thus, the ability to tailor the solubility of the delivery agent to the solubility of the bioactive agent would increase bioavailability of the bioactive agent.
Due to the hydrophilicity of many bioactive agents, such bioactive agents typically exhibit low bioavailability. Chemical modification of a native bioactive agent can result in an increase of lipophilicity, however, such modification imposes high costs for preparing and purifying the final product. If a delivery agent could increase lipophilicity of a native bioactive agent by simple mixing with the bioactive agent, it would allow increased bioavailiability and would also provide simplicity of preparation and low cost.
During oral delivery, a significant amount of delivery agent may precipitate under physiological conditions. The precipitated delivery agent is then unavailable for delivery of the bioactive agent to a point further along the GI tract and is also potentially toxic. Reducing the dose of delivery agent would allow more effective delivery of the bioactive agent with a low concentration of delivery agent and less toxicity.
Typical delivery agents do not interact with bioactive agents under physiological conditions. This is why a significant amount of delivery agent and/or enhancer are usually needed to deliver the bioactive agent. Increasing the ability of a delivery agent to interact with a bioactive agent would allow more effective delivery at much lower concentrations of delivery agent.
Maintaining or controlling the effective charge of a bioactive agent is crucial for increasing permeability of a bioactive agent through membranes. If a delivery agent could control the net charge of a bioactive agent by simple mixing of the delivery agent and the bioactive agent, it would allow more effective delivery of the bioactive agent.
The stability of a bioactive agent to proteolysis in the GI tract or at tissue surfaces can be a significant contributing factor for delivery efficiency. If a delivery agent could increase the stability of a bioactive agent toward proteolysis, it would allow more effective delivery.
A high aggregation state of a bioactive agent (especially for peptide and proteins drugs) results in low bioavailability after oral administration. If a delivery agent could alter the aggregation state of a bioactive agent, it would allow more effective delivery.
In view of the foregoing, it will be appreciated that providing compositions and methods for delivery of bioactive agents, wherein degradation and inactivation are inhibited, solubility problems are reduced, interaction of bioactive agents and delivery agents is increased, electrostatic charge is controlled, lipophilicity of bioactive agents is increased, and aggregation state of bioactive agents is altered, would be a significant advancement in the art.